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Safety and Efficacy Pilot Trial of the Anti-Viral and Anti-Tumor Activity of Velcade Combined With (R)ICE in Subjects With EBV and/or HHV-8 Positive Relapsed/Refractory AIDS-Associated Non-Hodgkin's Lymphoma


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Lymphoma

Thank you

Trial Information

Safety and Efficacy Pilot Trial of the Anti-Viral and Anti-Tumor Activity of Velcade Combined With (R)ICE in Subjects With EBV and/or HHV-8 Positive Relapsed/Refractory AIDS-Associated Non-Hodgkin's Lymphoma


OBJECTIVES:

Primary

- Evaluate the safety and overall lymphoma response rate of bortezomib in combination
with ifosfamide, carboplatin, and etoposide (ICE) with or without rituximab in patients
with Epstein-Barr Virus (EBV)- and/or human herpes virus-8 (HHV-8)- positive relapsed
or refractory HIV-associated non-Hodgkin lymphoma (NHL).

Secondary

- Evaluate the impact of bortezomib alone and in combination with rituximab) and ICE ([R]
ICE) on serum HIV viral loads and APOBEC3G levels.

- Estimate the impact of bortezomib alone and in combination with (R)ICE on EBV and HHV-8
lytic activation using serum viral loads.

- Estimate the median response duration and 1 year overall survival rate of patients
treated with this regimen.

- Evaluate the safety of bortezomib alone in patients with relapsed or refractory
AIDS-associated lymphomas.

- Correlate EBV/HHV-8 viral load changes with lymphoma response.

- Compare the above outcomes to a parallel protocol employing ICE with or without
rituximab in patients with EBV/HHV-8-negative AIDS-NHL to assess whether bortezomib has
additional effects beyond (R)ICE alone.

OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Patients are assigned
to 1 of 2 treatment groups.

- CD20-negative patients

- Part A: Patients receive bortezomib IV over 3-5 seconds on days 1 and 8,
dexamethasone IV and etoposide IV over 2 hours on days 8-10, and ifosfamide IV
continuously over 24-hours and carboplatin IV over 2 hours on day 9. Treatment
repeats every 28 days until the maximum tolerated dose (MTD) is determined.
Patients who tolerate the MTD of bortezomib may move on to part B.

- Part B: Patients receive bortezomib IV over 3-5 seconds at the MTD on days 1 and
8, dexamethasone IV on days 1-3 and 8, etoposide IV over 2 hours on days 1-3, and
ifosfamide IV continuously over 24-hours and carboplatin IV over 2 hours on day 2.
Treatment repeats every 21 days for up to 6 courses in the absence of disease
progression or unacceptable toxicity. Some patients may undergo hematopoietic stem
cell transplantation (HSCT).

- CD20-positive patients

- Part A: Patients receive bortezomib, dexamethasone, etoposide, ifosfamide, and
carboplatin as in the CD20-negative patients part A group.

- Part B: Patients receive rituximab IV on day 1. Patients also receive bortezomib,
dexamethasone, etoposide, ifosfamide, and carboplatin as in the CD20-negative
patients part B group. Some patients may undergo HSCT.

Patients undergo blood sample collection periodically for correlative studies. Samples are
analyzed for the effects of bortezomib on viral activation and replication via Taqman
polymerase chain reaction (PCR), and for quantification of APOBEC3G levels via western blot.
Similar studies are performed on the BCLB-1 EBV containing lines, as well as Daudi and other
EBV-transformed B-lymphocyte lines via quantitative viral DNA PCR.

Patients complete the Functional Assessment of Cancer Therapy/GOG-Neurotoxicity
Questionnaire, v4.0 at day 8 and week 4 of Part A and at least once per course of Part B for
assessment of neuropathic pain and/or peripheral neuropathy.

After completion of study treatment, patients achieving complete response (CR) are followed
at 2-4 weeks and then every 3 months for 1 year. Patients not achieving CR at completion of
study treatment and declining further antineoplastic treatment are followed at 2-4 weeks and
then every 3 months for 1 year.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed relapsed or refractory HIV-associated
non-Hodgkin lymphoma (NHL)

- Must have histologic or cytologic documentation of prior AIDS-associated NHL
(i.e., at time of diagnosis) for clinically relapsed and/or refractory disease
for which biopsy is not feasible

- Must have documented HIV seropositivity

- Must have documentation of Epstein-Barr Virus (EBV)- and/or human herpes virus-8
(HHV-8)- positive infection within the lymphoma (i.e., LMP-1, LANA expression,
or positive Epstein-Barr-encoded RNAs [EBERs])

PATIENT CHARACTERISTICS:

Inclusion criteria:

- ECOG performance status (PS) 0-2 OR Karnofsky PS 50-100%

- Life expectancy > 2 months

- ANC ≥ 1,000/mm³* (growth factor support allowed)

- Hemoglobin ≥ 8.0 g/dL* (growth factor support allowed)

- Platelet count ≥ 100,000/mm³

- Total bilirubin ≤ 1.5 mg/dL

- AST/ALT ≤ 2.5 times institutional upper limit of normal (ULN)

- Serum creatinine ≤ ULN

- Creatinine clearance ≥ 50 mL/min

- Negative pregnancy test

- Not pregnant or nursing

- Fertile patients must use effective contraception NOTE: *Patients with lymphomatous
involvement of the bone unable to meet hematologic criteria are allowed

Exclusion criteria:

- Peripheral neuropathy ≥ grade 2

- Uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Ongoing or active infection

- Opportunistic infections controlled by antimicrobial or suppressive therapy
allowed, unless the investigator judges the infection likely to become
life-threatening in the setting of multi-agent chemotherapy

- Symptomatic congestive heart failure

- Unstable angina pectoris

- NYHA class III or IV heat failure

- Myocardial infarction within the past 6 months

- Uncontrolled angina

- Severe uncontrolled ventricular or other cardiac arrhythmias

- Acute ischemia or active conduction system abnormalities by ECG

- Serious psychiatric or medical illness, that would interfere with study
compliance

- Social situations that would interfere with study compliance

- Acute active HIV-associated opportunistic infection requiring antibiotic treatment

- Mycobacterium avium or candidiasis allowed unless concurrent therapy with
moderate-to-strong CYP3A4 inducers or inhibitors is required

- Chronic myelosuppressive agent therapy allowed provided hematologic criteria are
met

- Hypersensitivity to compounds of similar chemical or biological composition to
bortezomib, boron, mannitol, ifosfamide, carboplatin, or etoposide

- Concurrent malignancy except carcinoma in situ of the cervix, in situ anal cancer,
nonmetastatic nonmelanoma skin cancer, or Kaposi's sarcoma not requiring systemic
chemotherapy

- Active hepatitis B infection (hepatitis B surface antigen-positive), unless 1 of the
following criteria are met:

- Able to start dual anti-hepatitis B adefovir and telbivudine therapy prior to
study

- Receiving dual anti-hepatitis B therapy for at least 12 weeks prior to study
with either agent active against HIV (i.e., entecavir, tenofovir, lamivudine, or
emtricitabine)

- Concurrent grapefruit juice/fruit or green tea

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Recovered from prior adverse effects due to agents administered more than 3 weeks
earlier

- Glucocorticoid therapy within the past 3 weeks allowed

- More than 3 weeks since prior chemotherapy

- More than 2 weeks since prior radiotherapy

- More than 14 days since prior and no other concurrent investigational agents (other
than bortezomib)

- No concurrent moderate-to-strong CYP3A4 inducers or inhibitors other than protease
inhibitors

- Concurrent stable (at least 12 weeks) antiretroviral regimen allowed

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of bortezomib

Outcome Time Frame:

Assessed at end of cycle 1 for each group of 3 subjects

Safety Issue:

Yes

Principal Investigator

Erin G. Reid, MD

Investigator Role:

Study Chair

Investigator Affiliation:

University of California, San Diego

Authority:

United States: Food and Drug Administration

Study ID:

CDR0000581078

NCT ID:

NCT00598169

Start Date:

November 2007

Completion Date:

November 2014

Related Keywords:

  • Lymphoma
  • AIDS-related diffuse large cell lymphoma
  • AIDS-related diffuse mixed cell lymphoma
  • AIDS-related diffuse small cleaved cell lymphoma
  • AIDS-related immunoblastic large cell lymphoma
  • AIDS-related lymphoblastic lymphoma
  • AIDS-related peripheral/systemic lymphoma
  • AIDS-related primary CNS lymphoma
  • AIDS-related small noncleaved cell lymphoma
  • Lymphoma
  • Lymphoma, Non-Hodgkin

Name

Location

Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
Virginia Mason Medical CenterSeattle, Washington  98111
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland  21231-2410
Cancer Research Center of HawaiiHonolulu, Hawaii  96813
USC/Norris Comprehensive Cancer Center and HospitalLos Angeles, California  90033-0804
Rebecca and John Moores UCSD Cancer CenterLa Jolla, California  92093-0658
Baylor University Medical Center - HoustonHouston, Texas  77030-2399
Montefiore Medical CenterBronx, New York  10467-2490
University of Miami Sylvester Comprehensive Cancer Center - MiamiMiami, Florida  33136
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer CenterColumbus, Ohio  43210-1240
UCLA Clinical AIDS Research and Education (CARE) CenterLos Angeles, California  90024
Pennsylvania Oncology Hematology Associates, Incorporated - PhiladelphiaPhiladelphia, Pennsylvania  19106
Emory Winship Cancer InstituteAtlanta, Georgia  30322
University of California at Davis Center for Aids Research and Education ServicesSacramento, California  95814
Thomas Street Health CenterHouston, Texas  77009
Northwestern Cancer CenterChicago, Illinois  60611